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Neurotherapeutics : the Journal of the... Jan 2022Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel...
Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.
Topics: Animals; Cytokines; Disease Models, Animal; Disease Progression; Drug Repositioning; Humans; Microglia; Neuroprotective Agents; Parkinson Disease; Rats; Substantia Nigra; Thalidomide; Tumor Necrosis Factor-alpha; alpha-Synuclein
PubMed: 35072912
DOI: 10.1007/s13311-022-01182-2 -
The Lancet. Haematology Feb 2022Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma.
METHODS
In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing.
FINDINGS
Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia).
INTERPRETATION
Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.
FUNDING
Oncopeptides AB.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Phenylalanine; SARS-CoV-2; Thalidomide; COVID-19 Drug Treatment
PubMed: 35032434
DOI: 10.1016/S2352-3026(21)00381-1 -
Pharmacotherapy Sep 2014Multiple myeloma is a hematologic malignancy characterized by plasma cell clonal expansion as well as end-organ damage due to increased levels of monoclonal proteins in... (Review)
Review
Multiple myeloma is a hematologic malignancy characterized by plasma cell clonal expansion as well as end-organ damage due to increased levels of monoclonal proteins in both the plasma and urine. The clinical syndrome is characterized by hypercalcemia, renal insufficiency, anemia, and bone involvement that leads to pathologic fractures. This progressive disease can result in significant patient morbidity and mortality. Despite advances with treatment options and autologous stem cell transplantation, multiple myeloma remains incurable. Current front-line therapies include proteasome inhibitors, immunomodulators, anthracyclines, and steroids. Due to the advent of the immunomodulatory agents thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, overall survival in patients with multiple myeloma has improved greatly. However, once patients progress through front-line therapy and have relapsed or refractory disease, treatment options have historically been very limited. Carfilzomib, a second-generation proteasome inhibitor, has shown impressive response rates as a single agent in the relapsed and refractory patient setting; this includes patients who are refractory to previous bortezomib therapy. In addition, a third-generation immunomodulator, pomalidomide, has also shown promising results in a similar patient population, including those patients who have been shown to be refractory to lenalidomide and bortezomib. Adverse effects of both of these medications have been considered tolerable in the relapsed or refractory population, especially considering the benefits that have been shown. Continuing clinical research will reveal the utility of these agents in combination regimens or in a front-line setting for patients with multiple myeloma.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Humans; Multiple Myeloma; Oligopeptides; Survival Rate; Thalidomide; Treatment Outcome
PubMed: 25044413
DOI: 10.1002/phar.1463 -
Cancer Research Dec 2018: Thalidomide-like drugs have been approved for the treatment of human multiple myeloma, with their direct antitumor effects and immunomodulatory functions well...
: Thalidomide-like drugs have been approved for the treatment of human multiple myeloma, with their direct antitumor effects and immunomodulatory functions well documented. However, the exact molecular mechanisms that govern these effects remain unclear. Here we demonstrate that pomalidomide promotes immune response by inhibiting expression of PD-L1. Pomalidomide inhibited PD-L1 expression on tumor cells to promote CTL activity and suppressed PD-L1 upregulation on antigen-presenting cells to prevent peptide-induced T-cell tolerance. Knockout of PD-L1 on tumor cells or in mice completely eliminated the immunomodulatory effect of pomalidomide. Furthermore, pomalidomide synergized with other immunotherapies to improve anticancer therapy. Taken together, this study identifies a new mechanism for the immunomodulatory functions of pomalidomide in cancer therapy. These results also offer a clinical approach for blocking PD-L1 induction and potentially promoting antitumor immunity. SIGNIFICANCE: These findings report that the immunomodulatory drug pomalidomide, widely used to treat myeloma and other cancers, enhances antitumor immunity by inhibiting PD-1/PD-L1 expression.
Topics: Animals; Antineoplastic Agents; B7-H1 Antigen; Cell Line, Tumor; Cytotoxicity, Immunologic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunity; Immunologic Factors; Immunomodulation; Melanoma, Experimental; Mice; Neoplasms; T-Lymphocyte Subsets; Thalidomide
PubMed: 30315115
DOI: 10.1158/0008-5472.CAN-18-1781 -
Annals of Oncology : Official Journal... Nov 2015While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of... (Review)
Review
While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials as Topic; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Risk Factors; Thalidomide
PubMed: 26216385
DOI: 10.1093/annonc/mdv325 -
Nature Medicine Feb 2024Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel...
Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody-drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478 .
Topics: Humans; Multiple Myeloma; Treatment Outcome; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Immunoconjugates; Thalidomide; Antibodies, Monoclonal, Humanized
PubMed: 38177852
DOI: 10.1038/s41591-023-02703-y -
Nature Chemical Biology Nov 2020The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although...
The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chromosomal Proteins, Non-Histone; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Lenalidomide; Multiple Myeloma; Mutation; Protein Binding; Proteolysis; RNA, Messenger; RNA, Small Interfering; Thalidomide; Time Factors; Transcription Factors; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 32958952
DOI: 10.1038/s41589-020-0645-3 -
British Journal of Neurosurgery Aug 2023A 77-year old female with a history of neurofibromatosis type 2 (NF2) was diagnosed with a spinal schwannoma that was managed conservatively over a decade. During this...
A 77-year old female with a history of neurofibromatosis type 2 (NF2) was diagnosed with a spinal schwannoma that was managed conservatively over a decade. During this time, follow up imaging revealed this lesion had been growing and the patient had become symptomatic from it necessitating surgical decompression. However, the patient had been diagnosed with multiple myeloma and underwent treatment with Pomalidomide chemotherapy which delayed surgery for the spinal schwannoma. Further imaging of the spine revealed significant regression in the size of the spinal schwannoma. This phenomenon has not previously been reported and this report aims to explore the implications of Pomalidomide in patients with NF2 related spinal schwannomas.
Topics: Female; Humans; Aged; Neurilemmoma; Neurofibromatosis 2; Treatment Outcome
PubMed: 32188281
DOI: 10.1080/02688697.2020.1742292 -
Journal of Clinical Pharmacology May 2015A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed...
A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed based on data from 6 clinical trials of pomalidomide (dose range, 0.5-10 mg) in healthy participants (n = 96) and patients with multiple myeloma (MM; n = 144). PPK data described herein suggest that systemic clearance of pomalidomide is comparable between healthy study participants and patients with MM. However, apparent peripheral volume of distribution and apparent intercompartmental clearance between central and peripheral compartments were 8- and 3.7-fold higher in patients with MM vs. healthy subjects, suggesting drug exposure is higher in peripheral compartments of patients with MM vs. healthy subjects. Covariate analysis suggested pomalidomide clearance is not affected by demographic factors except for gender, and it is unlikely this factor is clinically relevant. In addition, renal function as measured by creatinine clearance or renal impairment (RI) does not significantly affect clearance of pomalidomide. In conclusion, pomalidomide has robust pharmacokinetic exposure, not affected by demographic factors or renal impairment. Pomalidomide is preferentially taken up by tumors over healthy tissues in patients with MM.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Clinical Trials as Topic; Female; Humans; Immunologic Factors; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Multiple Myeloma; Renal Insufficiency; Sex Factors; Thalidomide
PubMed: 25556560
DOI: 10.1002/jcph.455 -
International Journal of Hematology Jul 2022In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with...
In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with relapsed/refractory multiple myeloma (RRMM) after their most recent regimen of lenalidomide-based therapy (NCT01946477). Patients received oral pomalidomide (4 mg daily), oral dexamethasone (20-40 mg weekly), and intravenously infused daratumumab (16 mg/kg). Median age was 67.5 years. All patients received prior lenalidomide per protocol; 89% received prior bortezomib. Twelve patients (67%) had lenalidomide-refractory disease, and 6 (33%) had lenalidomide-relapsed disease. Ten patients (56%) had only 1 prior treatment line. As of August 3, 2020, 15 patients (83%) were still on treatment; median follow-up was 8.1 months. Three patients (17%) discontinued treatment (2 for adverse events; 1 for major protocol deviation). Overall response rate (primary endpoint) was 83% (very good partial response or better, 61%). All patients had ≥ 1 grade 3/4 treatment-emergent adverse events, most commonly neutropenia (78%; febrile, 6%), leukopenia (28%), and lymphopenia (22%). Grade 3/4 infections occurred in 17%; 11% had pneumonia. In Japanese patients with RRMM, a triplet regimen of pomalidomide, dexamethasone, and daratumumab after early-line lenalidomide treatment failure showed high efficacy and safety consistent with the known safety profile.
Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Japan; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Thalidomide; Treatment Outcome
PubMed: 35429329
DOI: 10.1007/s12185-022-03338-4